Bottom Line:
Here, we examined the role of histamine in IL-6 production and histamine receptor activity in nasal fibroblasts, along with the mechanisms underlying these effects.Among the histamine-receptor specific antagonists, only the H1R antagonist significantly decreased IL-6 production in histamine-stimulated nasal fibroblasts.The data presented here suggest that antihistamines may be involved in the regulation of cytokines, such as IL-6, due to the role of histamine as an inflammatory mediator in nasal fibroblasts.

Affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Seoul, Korea.

ABSTRACT

Purpose: Based on the close relationship between histamine and interleukin 6 (IL-6), we hypothesized that histamine may regulate the production of cytokines, such as IL-6, during allergic inflammation. Here, we examined the role of histamine in IL-6 production and histamine receptor activity in nasal fibroblasts, along with the mechanisms underlying these effects.

Methods: Experiments were performed using nasal fibroblasts from 8 normal patients. RT-PCR was used to identify the major histamine receptors expressed in nasal fibroblasts. Fibroblasts were then treated with histamine with or without histamine-receptor antagonists, and monitored for IL-6 production using an ELISA. Four potential downstream signaling molecules, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB, were evaluated by Western blot, and a luciferase reporter assay.

Results: Elevated expression was seen for all histamine receptors, with IL-6 protein levels increasing significantly following histamine stimulation. Among the histamine-receptor specific antagonists, only the H1R antagonist significantly decreased IL-6 production in histamine-stimulated nasal fibroblasts. Histamine increased the expression level of phosphorylated p38 (pp38), pERK, and pJNK, as well as NF-κB induction. The H1R antagonist actively suppressed pp38 and NF-κB expression in histamine-induced nasal fibroblasts, but not pERK and pJNK. The p38 inhibitor strongly attenuated IL-6 production in histamine-stimulated nasal fibroblasts.

Conclusions: The data presented here suggest that antihistamines may be involved in the regulation of cytokines, such as IL-6, due to the role of histamine as an inflammatory mediator in nasal fibroblasts.

Mentions:
Histamine regulated HBp17/FGFBP-1 expression via the NF-κB binding site was evaluated using a luciferase reporter assay in which luciferase activity was driven by the HBp17/FGFBP-1 promoter. We observed a significant increase in HBp17/FGFBP-1 promoter activity following exposure to histamine (Fig. 7A). To confirm the effect of NF-κB inhibition on IL-6 production, we examined whether inhibition of NF-κB (Bay, 1 µM) could prevent histamine-induced IL-6 production in nasal fibroblasts using an ELISA. Cells were pretreated with fexofenadine and Bay for 1 hour, and then stimulated with histamine for 24 hours. Bay significantly blocked the increased production of IL-6 in histamine-stimulated nasal fibroblasts (Fig. 7B), consistent with a role for NF-κB in IL-6 production.

Mentions:
Histamine regulated HBp17/FGFBP-1 expression via the NF-κB binding site was evaluated using a luciferase reporter assay in which luciferase activity was driven by the HBp17/FGFBP-1 promoter. We observed a significant increase in HBp17/FGFBP-1 promoter activity following exposure to histamine (Fig. 7A). To confirm the effect of NF-κB inhibition on IL-6 production, we examined whether inhibition of NF-κB (Bay, 1 µM) could prevent histamine-induced IL-6 production in nasal fibroblasts using an ELISA. Cells were pretreated with fexofenadine and Bay for 1 hour, and then stimulated with histamine for 24 hours. Bay significantly blocked the increased production of IL-6 in histamine-stimulated nasal fibroblasts (Fig. 7B), consistent with a role for NF-κB in IL-6 production.

Bottom Line:
Here, we examined the role of histamine in IL-6 production and histamine receptor activity in nasal fibroblasts, along with the mechanisms underlying these effects.Among the histamine-receptor specific antagonists, only the H1R antagonist significantly decreased IL-6 production in histamine-stimulated nasal fibroblasts.The data presented here suggest that antihistamines may be involved in the regulation of cytokines, such as IL-6, due to the role of histamine as an inflammatory mediator in nasal fibroblasts.

Affiliation:
Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Seoul, Korea.

ABSTRACT

Purpose: Based on the close relationship between histamine and interleukin 6 (IL-6), we hypothesized that histamine may regulate the production of cytokines, such as IL-6, during allergic inflammation. Here, we examined the role of histamine in IL-6 production and histamine receptor activity in nasal fibroblasts, along with the mechanisms underlying these effects.

Methods: Experiments were performed using nasal fibroblasts from 8 normal patients. RT-PCR was used to identify the major histamine receptors expressed in nasal fibroblasts. Fibroblasts were then treated with histamine with or without histamine-receptor antagonists, and monitored for IL-6 production using an ELISA. Four potential downstream signaling molecules, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB, were evaluated by Western blot, and a luciferase reporter assay.

Results: Elevated expression was seen for all histamine receptors, with IL-6 protein levels increasing significantly following histamine stimulation. Among the histamine-receptor specific antagonists, only the H1R antagonist significantly decreased IL-6 production in histamine-stimulated nasal fibroblasts. Histamine increased the expression level of phosphorylated p38 (pp38), pERK, and pJNK, as well as NF-κB induction. The H1R antagonist actively suppressed pp38 and NF-κB expression in histamine-induced nasal fibroblasts, but not pERK and pJNK. The p38 inhibitor strongly attenuated IL-6 production in histamine-stimulated nasal fibroblasts.

Conclusions: The data presented here suggest that antihistamines may be involved in the regulation of cytokines, such as IL-6, due to the role of histamine as an inflammatory mediator in nasal fibroblasts.